Proteomic Identification of Protein Targets for 15-Deoxy-Δ12,14-Prostaglandin J2 in Neuronal Plasma Membrane

15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is one of factors contributed to the neurotoxicity of amyloid β (Aβ), a causative protein of Alzheimer's disease. Type 2 receptor for prostaglandin D2 (DP2) and peroxysome-proliferator activated receptorγ (PPARγ) are identified as the membrane receptor and the nuclear receptor for 15d-PGJ2, respectively. Previously, we reported that the cytotoxicity of 15d-PGJ2 was independent of DP2 and PPARγ, and suggested that 15d-PGJ2 induced apoptosis through the novel specific binding sites of 15d-PGJ2 different from DP2 and PPARγ. To relate the cytotoxicity of 15d-PGJ2 to amyloidoses, we performed binding assay [3H]15d-PGJ2 and specified targets for 15d-PGJ2 associated with cytotoxicity. In the various cell lines, there was a close correlation between the susceptibilities to 15d-PGJ2 and fibrillar Aβ. Specific binding sites of [3H]15d-PGJ2 were detected in rat cortical neurons and human bronchial smooth muscle cells. When the binding assay was performed in subcellular fractions of neurons, the specific binding sites of [3H]15d-PGJ2 were detected in plasma membrane, nuclear and cytosol, but not in microsome. A proteomic approach was used to identify protein targets for 15d-PGJ2 in the plasma membrane. By using biotinylated 15d-PGJ2, eleven proteins were identified as biotin-positive spots and classified into three different functional proteins: glycolytic enzymes (Enolase2, pyruvate kinase M1 (PKM1) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH)), molecular chaperones (heat shock protein 8 and T-complex protein 1 subunit α), cytoskeletal proteins (Actin β, F-actin-capping protein, Tubulin β and Internexin α). GAPDH, PKM1 and Tubulin β are Aβ-interacting proteins. Thus, the present study suggested that 15d-PGJ2 plays an important role in amyloidoses not only in the central nervous system but also in the peripheral tissues

Understanding Sensory-Motor Disorders in Autism Spectrum Disorders by Extending Hebbian Theory: Easy Formation of Rigid-Autonomous Phase Sequences (RAPS)

Autism spectrum disorder is a neuropsychiatric disorder characterized by 1) persistent deficits in social communication and social interaction; and 2) restricted, repetitive patterns of behavior, interests, or activities. The symptoms invariably appear early in development and cause significant impairment in social, occupational, and other important functions. Various abnormalities in the genetic, neurological, and endocrine systems of patients with autism spectrum disorder have been reported as the etiology; however, no clear factor leading to the onset of the disease has been identified. Additionally, higher-order cognitive dysfunctions, which is represented by a lack of theory of mind, sensorimotor disorders, and memory-related disorders (e.g., flashbacks), have been reported in recent years, but no theoretical framework has been proposed to explain these behavioral abnormalities. In this study, we extended Hebb’s theory in biopsychology to provide a theoretical framework that comprehensively explains the various behavioral abnormalities observed in autism spectrum disorder. Specifically, we proposed that a wide range of symptoms in autism spectrum disorder may be produced by the easy formation of rigid-autonomous phase sequences (RAPS) in the brain. Through the theory of RAPS formation, we explained a biopsychological mechanism that is a target for the treatment of autism spectrum disorders

Understanding Sensory-Motor Disorders in Autism Spectrum Disorders by Extending Hebbian Theory: Formation of a Rigid-Autonomous Phase Sequence (RAPS)

Autism spectrum disorder is a neuropsychiatric disorder characterized by 1) persistent deficits in social communication and social interaction and 2) restricted, repetitive patterns of behavior, interests, or activities. The symptoms invariably appear in early childhood and cause significant impairment in social, occupational, and other important functions. Various abnormalities in the genetic, neurological, and endocrine systems of patients with autism spectrum disorder have been reported as the etiology; however, no clear factor leading to the onset of the disease has been identified. Additionally, higher-order cognitive dysfunctions, which are represented by a lack of theory of mind, sensorimotor disorders, and memory-related disorders (e.g., flashbacks), have been reported in recent years, but no theoretical framework has been proposed to explain these behavioral abnormalities. In this study, we extended Hebb’s biopsychology theory to provide a theoretical framework that comprehensively explains the various behavioral abnormalities observed in autism spectrum disorder. Specifically, we propose that a wide range of symptoms in autism spectrum disorder may be caused by the formation of a rigid-autonomous phase sequence (RAPS) in the brain. Using the RAPS formation theory, we propose a biopsychological mechanism that could be a target for the treatment of autism spectrum disorders

Monoaminergic and neuropeptidergic neurons have distinct expression profiles of histone deacetylases.

Monoaminergic and neuropeptidergic neurons regulate a wide variety of behaviors, such as feeding, sleep/wakefulness behavior, stress response, addiction, and social behavior. These neurons form neural circuits to integrate different modalities of behavioral and environmental factors, such as stress, maternal care, and feeding conditions. One possible mechanism for integrating environmental factors through the monoaminergic and neuropeptidergic neurons is through the epigenetic regulation of gene expression via altered acetylation of histones. Histone deacetylases (HDACs) play an important role in altering behavior in response to environmental factors. Despite increasing attention and the versatile roles of HDACs in a variety of brain functions and disorders, no reports have detailed the localization of the HDACs in the monoaminergic and neuropeptidergic neurons. Here, we examined the expression profile of the HDAC protein family from HDAC1 to HDAC11 in corticotropin-releasing hormone, oxytocin, vasopressin, agouti-related peptide (AgRP), pro-opiomelanocortin (POMC), orexin, histamine, dopamine, serotonin, and noradrenaline neurons. Immunoreactivities for HDAC1,-2,-3,-5,-6,-7,-9, and -11 were very similar among the monoaminergic and neuropeptidergic neurons, while the HDAC4, -8, and -10 immunoreactivities were clearly different among neuronal groups. HDAC10 expression was found in AgRP neurons, POMC neurons, dopamine neurons and noradrenaline neurons but not in other neuronal groups. HDAC8 immunoreactivity was detected in the cytoplasm of almost all histamine neurons with a pericellular pattern but not in other neuropeptidergic and monoaminergic neurons. Thus, the differential expression of HDACs in monoaminergic and neuropeptidergic neurons may be crucial for the maintenance of biological characteristics and may be altered in response to environmental factors

Balancing authority and autonomy in higher education by implementing an agile project management approach

This article develops and implements an agile management approach in higher education. Such an approach follows core practices, such as project plans. The project manager has to identify the agility drivers that represent changes and pressures; prioritize agility capabilities to take advantage of changes; identify agility providers to obtain agility capabilities; and make managerial choices to manage the project. The object of the study is a department at a public university; it must follow the institutional framework and laws, and the university and faculty decisions, strategies and policies. The article discusses how agility can be created in such circumstances

Expression of HDAC5 and -6 in monoaminergic and neuropeptidergic neurons.

<p>The HDAC immunolocalizations (green) were visualized with a neuronal marker (magenta) and Hoechst stain (blue). <b>A:</b> HDAC5 was detected in the nucleus (arrow) and cytoplasm (open arrow) of AgRP neurons, with punctate immunoreactivity (arrowheads) in the ARC. <b>B:</b> HDAC5 was detected in the nucleus (arrow) and cytoplasm (open arrow) of POMC neurons, with punctate immunoreactivity (arrowheads) in the ARC. <b>C:</b> HDAC5 was detected in the nucleus (arrow) and cytoplasm (open arrows) of dopamine neurons. <b>D:</b> HDAC5 was detected in the cytoplasm (open arrows) of serotonin neurons, with punctate immunoreactivity (arrowhead) in the DR. <b>E</b>: Strong HDAC5 immunoreactivity was observed in the cytoplasm (open arrows) of noradrenaline neurons. <b>F</b>: Granular HDAC5 immunoreactivities were observed in the dendrites (open arrows) in the LHA. <b>G</b>: HDAC6 was detected in the nuclei (arrows) and cytoplasm (open arrows) of CRH neurons, with abundant HDAC6-immunoreactive puncta (arrowheads) in the PVN. <b>H</b>: HDAC6 was detected in the cytoplasm (open arrow) of oxytocin neurons, with punctate immunoreactivity (arrowheads) in the PVN. <b>I</b>: HDAC6 was detected in the nucleus (arrow) and cytoplasm (open arrow) of vasopressin neuron. <b>J:</b> HDAC6 was detected in the nucleus (arrow) and cytoplasm (open arrow) of orexin neurons, with punctate immunoreactivity (arrowheads) in the LHA. <b>K:</b> HDAC6 was detected in the nucleus (arrow) and cytoplasm (open arrow) of AgRP neurons. <b>L:</b> HDAC6 was detected in the nucleus (arrow) and cytoplasm (open arrow) of POMC neuron, with punctate immunoreactivity (arrowheads) in the ARC. <b>M:</b> HDAC6 was detected in the nucleus (arrow) and cytoplasm (open arrow) of histamine neurons, with punctate immunoreactivity (arrowheads) in the TMN. <b>N:</b> HDAC6 was detected in the nuclei (arrows) and cytoplasm (open arrow) of dopamine neurons. <b>O:</b> HDAC6 was localized in the nuclei (arrows) and cytoplasm (open arrow) of noradrenaline neurons, with punctate immunoreactivity (arrowheads) in the LC. <b>P:</b> Some of HDAC6-immunoreactive puncta were colocalized with PSD95-immunoreactive puncta (open arrows) in the LHA. Scale bars indicate 10 µm (A–E, G–O) and 5 µm (F, P).</p

HDACs Immunoreactivities in Monoaminergic and Neuropeptidergic Neurons.

<p>The percentage of immunoreactive cells was assessed at the confocal laser scanning microscopy. Values are means ± S.E.M. Nuclear or cytoplasmic localization of HDACs was determined based on the colocalization with Hoechst 33342. The extent of HDACs immunoreactivities was determined on the intensity and area of the immunoreactivities: “+++”, strong immunoreactivity; “++”, moderate immunoreactivity; “+”, weak immunoreactivity; “−“, no immunoreactivity above background.</p

Differential HDAC expression within the monoaminergic and neuropeptidergic neurons of adult male mice.

<p>Differential HDAC expression within the monoaminergic and neuropeptidergic neurons of adult male mice.</p